Background: Hepatocellular carcinoma (HCC) is considered to be one of the most aggressive malignancies. Several studies have shown that dickkopf-1 (DKK1) is overexpressed in HCC tissue. Objective and Methods: The present study aimed at demonstrating the diagnostic efficacy of serum levels of DKK1 in HCC in comparison to alpha fetoprotein (AFP). Eighty individuals were included in the present study, and categorized to three groups: Group I: 40 patients with HCC on top of viral liver cirrhosis, Group II: 20 patients with viral induced liver cirrhosis without HCC, and Group III: 20 healthy individuals. Serum levels of AFP and DKK1 were measured and compared in all groups. Results: The values of AFP and DKK1 in group I were statistically higher than those in groups II and III. At the optimum value of 11.7 ng/ml, the sensitivity and specificity of serum AFP were 70.0% and 87.5%, respectively. DKK1 had higher sensitivity (80.0%) and specificity (90.0%) than AFP, at the cut-off value of 1.28 ng/ml for the diagnosis of HCC. Area under the curve (AUC) was higher in DKK1 (0.811) than AFP (0.779) when discriminating between group I and other groups. It was noted that the combination of both markers had a higher sensitivity and specificity, and a larger AUC than each alone. Conclusion: Serum DKK1 is a promising biomarker and is superior to AFP for HCC diagnosis. Combination of AFP and DKK1 improved the accuracy of HCC diagnosis in relation to each test alone.